Hydroxy-benzimidazoles and method for their preparation



Patented Dec. 22, 1953 HYDROXY-BENZIMIDAZOLES AND METHOD FOR THEIR PREPARATION Vsevolod Tulagin, Phillipsburg, N. 5., assignor to General Aniline & Film Corporation, New York,

N. Y., a corporation of Delaware N Drawing. Application November 22, 1949, I Serial N0. 128,930

11 Claims. (01. 260309.2)

This invention relates to novel compounds of the hydroxybenzimidazole series and a process for their preparation. The novel compounds of this invention are hydroxy-benzimidazoles (either in by reaction with aromatic diazo compounds. The compounds are particularly useful, and especially the preferred class thereof mentioned above, as coupling components in the preparation of diazotype light-sensitive layers in which they form image colorations by coupling with a lightsensitive diazo compound. When employed for the latter purpose, they yield dense, brilliant image colorations fast to light and washing, in I which the background areas resist discoloration ble with the other components of diazotype sensitizing compositions in aqueous solutions commonly employed for this purpose, and the photothe form of free bases or as saltsthereof with 5 sensitized materials obtained therewith are stable acids), wherein the hydroxyl group occupies a against premature coupling or discoloration in position in th benzene ring ortho to a nitrogen storage. of the imidazole ring, said benzene ring having Hydroxy-benzimidazoles were known heretoan unsubstitutedposition para to the hydroxyl fore, but previously known compounds contained group, and the remaining positions (positions 5 the hydroxyl group in 5- or 6- position, and were and 6) occupied, respectively, by'hydrogen and a unsatisfactory as azo coupling components. member of the group consisting of hydrogen, The compounds of this invention are prepared a kyl and aryl radicals; and aid imidazole ring from lower alkyl (e. g. methyl or ethyl) ethers having the 2- position occupied by hydrogen, an of 2,3-diaminophenol or nuclear substitution alkyl an a yl r p, nd a ni ro n om 00- 1 products thereof, containing an alkyl or aryl cupied by hydrogen or an alkyl or aralkyl group. group in 5- or 6- position. These diaminophenol Thus, the pe n t ve in the others can be obtained from the corresponding form of their free bases, can be represented by 2,3-dinitrophenol ethers, which are prepared acthe following formula: cording to the procedure of Meldola nd Ey X J. 'C. S., vol. 81 (1902), page990, involving dinitration of a p'-acetamidophenol ether, and reaction with sufuric acid, ethanol and a nitrite to replace the acetamido group with hydrogen. The Y nitro groups in the resulting 2,3-dinitrophenol \N 1 other are then reduced to amino groups, e. g. by I 2': 1'12 treatment with hydrogen in the presence ofda hydrogenation catalyst such as platinum oxi e. 21 12233 2553; i 23 22.22 .33? In accordance with the invention, the resulting sents a member of theclass consisting of H, alkyl M ether 15 w1th an and 'q groups, one X represents OH d phatic or aromatic carboxy acid anhydride until the other H, and one Y represents H and the other the correspondmg ortho'auEoxy'benzlmldazole is Y represents a member of the group consisting of formed- The alkoxy f hydrolyzed to H, alkyl and aryl radica1s an hydroxyl group by heating with concentrated Preferred compounds in accordance with the aqueous acld- The benzlmldazole invention are 2-alkyland Z-aryl-ortho-hydroxy hydrobromlde thus formed can be f fi benzimidazoles, as defined above, in which t the corresponding free base by treatment with an alkyl and aryl groups (represented by R1 i th alkaline neutralizing agent, and the free base can foregoing formula) are hydrocarbon radicals. be neutra'hzed deslred, Wlth another 301d The term ortho-hydroxy-benzimidazole is emform the benzimidazole salt of the latter ac1d. ployed herein to signify a hydroxy-benzimidazole to Direct eonversien 0f the hydrexy-benzlmldazole in which the hydroxyl group is in ortho position hydrobromide, initially formed, to salts of strongto a nitrogen f t imidazoh; ring. er mineral acids, such as hydrochloric acid, can

The compounds of the invention are valuable as also be efieeted by tin the benzimidazole hydyestufi intermediates, particularly as coupling drobremide w th t strong mineral acid until components in the preparation of azo dyestuffs- 15 the hydrobromle a is p d.

The carboxy acid anhydride which reacts with the 2,3-diaminophenol ether determines the nature of the substituent in the 2- position of the benzimidazole nucleus. Thus, acetic acid anhydride yields a 2-methyl-substituted benzimidaable; and homologues :in which higher alkyl groups occupy the 2- position result from using anhydrides of the higher homologues of acetic acid. Benzimidazoles of the invention which contain hydrogen in 2-'position are best obtained by employing a mixed anhydride oi formic and acetic acid, and those containing an aryl (e. g. phenyl radical) in 2- position are conveniently prepared by employing a mixed anhydride of acetic acid with the corresponding aryl carboxylic acid such as benzoic 'or toluic acid.

One of the nitrogen atoms of the benzimidazole ring can be alkylated, if desired, by reaction of the alkoxy benzimidazole, formed as an intermediate, with an alkyl or aralkylhalidesuch .as.

ethyl bromide or benzyl chlori'de,in an. inert s'olvent such as alcohol. The alkoxy group in the resulting product can then be'nonvertedito 'ayphenolic hydroxy group in the manner described above.

Purification of the products can beconvenient- 1y effected by conversion of the hydrobromidetto the hydrochloride, and recrystallization of the latter from aqueous solution.

The following examples illustrate preferred methods for preparing the :compounds or this .invention. In the examples, parts are bywei'ght unless otherwise 'zspecified, rand by .volume signfy the volume of :an :equa1nurnber of .parts by'iweight :of water.

w Preparation of 2f3-dicmmoanisolehydrochloride 8 parts of 2,3 dinitro d acetamido anisole (prepared by the method :of Meldola and Eyre (loc. cit.) were added to :an agitated mixture of 37 parts concentrated :sulfuric acid with '80 parts by volume of absolute ethyl 781001101, while cooling the mixture. The reaction mixture was then heated overa steam bath until :complete solution was obtained, requiring about 2 hours, 72116 then cooledto 045 C. .A-solutioniofxz'l-parts ofsodium 'nitriteiinifx parts of water was added, and after a '10 .minutes, the mixture was heated to boiling. fGaseous ."nitrogen' was evolved and when the evodution subsided, the mixture was poured into an equal volume of :water. .Azsuspension'of 2,3di-

nitroanisole was Zthus Jobtained, from which the product was recovered 'by'filtration, washed, :and purified by recrystallization :from ethyl alcohol.

13 ,parts-of 2,3-dinitroanisole were dissolved in 100 partsby weight of ethyl alcoholwhichwas .-suspended-0.2 part of alplatinum oxide hydrogenation catalyst (-Adamsl, and the mixture hydrogenated 'at :60 pounds pressure with hydrogen for 3 hours. 10 parts :by volume of concentrated hydrochloric acid were added, and the mixture evaporated to dryness. The hydrochloride obtained as a residue was dissolved in 20 parts of water, the'solution diluted with 80 :parts by volume of absolute ethanol, the diluted solution decolorized by treatment with active charcoal, and after filtering, 30 parts by volume of concentrated hydrochloric acid were added to the filtrate which was then cooled. The crystalline-hydrochloride of-2,3-diaminoanisole separated from the solution and was recovered .by filtration and washing with absolute alcohol, and dried.

benzimidazc'le 6.5 parts of .2,3-diaminoanisole hydrochloride and 32 parts by volume of :acetic anhydride were 'mixed in arefiux apparatusand heated to boiling for 45 minutes. 30 parts of 48% aqueous hydro- 'bromic acid were cautiously added, and 'the mixture heated to boiling under reflux for 4 hours.

.By employing an equal amount of the mixed.

anhydride of acetic and formic acids instead of acetic anhydride in the foregoing example, orthohydroxy-benzimidazole hydrochloride is obtained in like manner.

Similarly, by substituting an 'equimolecular amount "of :propioriic 'anh'ytiri'de :or or buty-ric an- .hydride .for the :aoetic r'anhydrid'e :of the "example, :2-ethylortho hydroxy benzimidazole and VZ-proip'yl-orthohydroxymenzimidazcle can :be obtaine'diin the' formfotitheir hydrochlorides.

:By employing an equimolecular amount or "the 'mixedeanhydride eo'f benzoicacid and acetic acid instead of the acetic anhydride of the example, 2*phenyl ortho=hydroxy=benzimidazole hydrochloride :is obtained. Elie .mixed :ianhydr ide of acetic "acid'andbenzoic acid can The prepared beforehand, or more conveniently, the reaction mixture, .by reaction of benzo'yl chloride with an fequimolecular amount of -sodium acetate. By substituting 3- aor *enitrobenzoyl 'chlor ide ror benzoyl chloridezin s'uch aiprocess, the 2- or "4' -nitropheny1) ortho-hymoxy=benaimidazole hydrochloride is produced.

EXAMPLE 2 Z-methoxy-5-acetaniidotoluene was dinitrated, and the resulting 3,4-dinitro compound was treated in accordance with th'e'pro'cedure described in Examples 1(a) and 1(1)). "The final product thus obtained was 2,6-dimethyl-ortho-hydroxy-benzimidazole hydrochloride.

F2-hydroxy 5=nitro=biphenyl "was "prepared "as described by iisorsehe and 'Schel'den in Ber. 5 page 600, and was converted to the corresponding methyl ether by heating the corresponding sodium phenolate with methyl iodide. The resulting nitro'ineth'yl ether is reduced to the corresponding amine compound, the amino group 'acjetylated and the actylarflfiio compound'dir'iitrated in the manner described by Meldola and Eyre (loo. citl'). "The 2-methoxy 3f4 dinitro 5 acetamino-'blphenyi thus obtained was processed in the same manner as the 2;3-dinltro=4=aeetamidc- 'an'isole of Examples 1 m) and 1%), whereby '2- methyl-6-pherlyl 7=hydrexy benziriiida'z'ole hydrochloride was obtained as the final product.

6.5 :parts of -2,3-diaminoanisole hydrochloride, obtained in accordance with Example 1 (a), was refluxed with 32 parts by volume'of acetic anhydride for 45 minutes. The solution was evaporated to dryness to yield 2-m'ethyl-ortho-meth- 'oxy-benzimidazole hydrochloride. :Ehe residue was taken up in 'absolute amen-o1 and converted to the free base by reaction of the calculated amount or sodium carbonate, and the insoluble On evaporation to dryness, a residue was 0b- 7 sodium salts iilteredJ-rom the alcoholic solution ture to dryness, the residue was mixed with '50 parts by volume of 40% hydrobromic acid, and heated under reflux for 20 hours. After evaporating to dryness, the residue was taken up in a small amount of water, and the solution cooled, whereupon a crystalline product separated which was recovered by filtration. The product thus obtained was 2-methyl-N-ethyl-ortho-hydroxybenzimidazole hydrobromide. I

The products of the foregoing examples are susceptible to coupling in the iunsubstitutedpositionof the benzene ring, para to thehy'dro'xyl group, with aromatic diazo components to yield azo compounds. Substituents in the 5- or 6- position of the benzimidazole nucleus can be varied by employing 5- or G-substituted 2,3-diamonoanisoles or phenetoles as starting materials. Such substitutes are especially alkyl and aryl radicals as illustrated in the foregoing examples.

In the reduction of the 2,3-dinitrophenol ethers to the corresponding diamino compounds serving as intermediates in the process of this invention, catalytic hydrogenation disclosed in the examples offers a convenient procedure, but other methods of reduction can be used, as for example, reaction with metals such as tin, zinc or iron in the presence of hydrochloric acid.

In converting the alkoxybenzimidazoles to the corresponding hydroxy-benzimidazoles, the concentrated aqueous hydrobromic acid employed should have a concentration of at least 25%, the concentration being of the order of 40 to 0% as disclosed in the examples.

Other N-substituted derivatives are obtained by the process of Example 4, employing other alkyl halides, or aralkyl halides such as benzyl chloride or bromide, instead of ethyl bromide.

The benzimidazoles specified in the claims signify these compounds in the form of free bases, as well as salts thereof with acids. The free bases can be obtained from the salts by the procedure employed in Example 4 to convert the intermediate alkoxy-benzimidazole hydrochloride to the corresponding free base.

Other variations and modifications, which will be obvious to those skilled in the art, can be made in the procedure disclosed in the examples without departing from the scope or spirit of the invention.

I claim:

1. An o-hydroxybenzimidazole having, in the form of its free base, the following formula:

wherein R1 represents a member of the class consisting of H, alkyl and aryl groups, R2 represents a member of the class consisting of H, alkyl and aralkyl groups, one X represents OH and the other H, and one Y represents H and the other Y represents a member of the group consisting of H, alkyl and aryl radicals.

A- 2-alkyl-substituted o-hydroxybenzimida- .zole having the following formula:

' whereinR representsan alkylgroup, one X repazole "having-the following formula:

wherein Ar represents an aryl group, one X represents OH and the other X represents H.

4. 2 methyl-o-hydroxybenzimidazole having the following formula:

C-CH2 5. Z-phenyl o hydroxybenzimidazole having the following formula:

6. A process for preparing an ortho-hydroxybenzimidazole, which comprises heating an anhydride of an organic monocarboxylic acid of the class consisting of fatty acids and carbocyclic monocarboxylic acids with a lower alkyl ether of a 2,3-diaminophenol, in which the 4- position is substituted by hydrogen and the remaining 5- position and 6- positions are occupied, respectively, by hydrogenand a member of the group consisting of hydrogen, alkyl, and aryl groups, and heating the resulting orthoalkoxy benzimidazol in concentrated aqueous hydrogen bromide to effect conversion of the alkoxy group to a phenolic hydroxyl group.

7. A process as defined in claim 6, including the further step of heating the ortho-alkoxy benzimidazole with an alkyl bromide to introduce an alkyl grou on a nitrogen atom thereof, prior to heating with concentrated aqueous hydrogen bromide.

8. A process for preparing a 2-aryl-orthohydroxy-benzimidazole, which comprises heating 2,3-diaminoanisole with a carbocyclic monocarboxylic acid anhydride, and heating the resulting 2 aryl-ortho methoxy benzimidazole with concentrated aqueous hydrozen bromide to effect conversion of the carboxyl group to a phenolic hydroxyl group.

9. A process for preparing 2-alkyl-orthohydroxy-benzimidazole, which comprises heating 2,3-diaminoanisole with a fatty acid anhydride, and heating the resulting 2-aryl-ortho-methoxy- 'ben'z'imida'z'loie with s ems hy- 11. A process for preparing 2-pheny1-ortho- 10 hydroxy-benz'imidaizole, which comprises heating 2,3-diami'noaniso1e with the mixed a-nhydride of 'benzoic acid and acetic "acid a'nd healting the resulting 2-pheny1 ortho methoxy-benzimidazole with concentrated aqueous hydrogen bromide.

VSEVOLOD TULAGIN.

Re'ferences 'Cited in the "file of this patent UNITED STATES PATENTS Number Name Date 2,545,687 Mar. 20, 1951' 2,548,845 :Neumann Apr. 10, 1951 FOREIGN PATENTS Number Country Date 359,063 Great Britain Oct. 2 1931 OTHER REFERENCES Beilstein: Qr'ganische .Chemie, Vierte Auflage, V0123; p. 385, citing Cohn, Berichte 32, page 2243. Weygand: Organic Preparations, 1945, page Degerin'g; "Outline of Organic Chemistry, 4th ed., "p. 196.

- en a. 

1. AN O-HYDROXYBENZIMIDAZOLE HAVING, IN THE FORM OF ITS FREE BASE, THE FOLLOWING FORMULA: 